The present invention is generally in the field of methods and compositions of treatment of neurological disorders, such as epilepsy and stroke, and neuroendocrine disorders, such as obesity. The present invention is also in the field of methods and compositions for modulating gene expression, such as gene expression of the N-methyl-D-aspartate (NMDA) receptor and the transcription factor, Krox-24.
Methods for treating a variety of neurological disorders have focused on the use of pharmaceutical agents which interact with neurological receptors such as the NMDA receptor, neurotransmitter transporters, such as the serotonin or dopamine transporters, various ion channels, or compounds which act to supplement or replace a neurotransmitter such as dopamine. Numerous treatments have been proposed for treatment of disorders such as Alzheimer's, Parkinson's and damage due to stroke, all without lasting success.
Due to NMDA receptors central involvement in the cascade leading to neuronal death following a variety of cerebral insults, pharmacological NMDA receptor antagonists have been evaluated for potential clinical utility. These drugs have shown to be effective in many experimental animal models and some of the compounds have moved into clinical trials (Schehr (1996) Nat. Biotechnol. 14:1549-1554). The initial enthusiasm for this approach has, however, waned as the therapeutic ratio for most NMDA antagonists is poor since at clinically effective doses they have been associated with significant adverse effects thereby limiting their utility (Schehr (1996) Nat. Biotechnol. 14:1549-1554).
An alternative approach to modify the function of brain proteins has been the use of antisense oligonucleotides or RNA antisense expressing vectors as well as local application of antibodies targeting the specific protein. Some of these approaches have been used to block or translationally suppress NMDA receptor expression and appear effective in a variety of model systems (Wahlestedt et al. (1993) Nature 363:260-263; Sun and Faden (19950 Brain Res. 693:163-168). However, these therapies generally have transient and limited efficacy.
Therefore a need exists to provide an alternative method of treatment for neurological disorders such as epilepsy, stroke, neuropsychiatric and neurodegenerative disorders. A need also exists to target specific antigens within the brain and modify their function.